Uncontrolled cell proliferation is a predominant feature of breast cancer. In fact, it is the deregulation of signaling pathways controlling cell proliferation that lead to the course of oncogenic transformation and tumorigenesis. The ErbB family of growth factor receptors (ErbB1-4) and their ligands have been strongly implicated in the genesis of a number of human carcinomas. The ErbB receptors mediate cellular responses to growth factors through their intracellar signaling domain. A significant effort has been made to identify the signaling molecules that directly interact with these domains and to understand the mechanism by which they transfer ErbB-mediated signals from the cell surface to the nucleus. ErbB3 expression levels have been correlated with certain human cancers that are aggressive and unresponsive to drug therapies. The ErbB3 receptor possesses a large C-terminal tail which, in the activated state, recruits a number of intracellular oncogenic signaling molecules. However, identification of the cellular proteins those bind the ErbB3 signaling domain has never been methodically carried out. Our lab has devised a method by which to systematically screen for effectors that mediate ErbB3 oncogenic activity. Using this approach, we have discovered novel cellular proteins that interact with activated ErbB3. The function of these proteins in ErbB3- dependent cell activation is completely unknown. However, due to their association with the activated form of ErbB3, we suspect that they are involved in mediating or regulating cell proliferation signals generated from ErbB3. Here, we propose to study the function and mechanism of action of these proteins in human cancer cells. These studies should provide fundamental information about the mechanism of human cancer development and could offer new therapeutic strategies for preventing the progression of human cancer in the clinic.